The invention relates to an absorption enhancer for the large intestine.
Physiologically active polypeptides or oligonucleotides have hitherto been developed as a preparation for an intravenous, intranasal or rectal administration. However, owing to the inconvenience in using these administration forms, the dosage form is most desired to be an oral administration form.
In order to formulate a physiologically active polypeptide or an oligonucleotide into a dosage form for oral administration, first it is necessary that the polypeptide or oligonucleotide is not degraded in the digestive tract. For this reason, it is important to target a site in which the degradation activity for these physiologically active substances is as low as possible.
On the other hand, owing to the fact that the large intestine has extremely low protease activity and that drug absorption is greatly improved by addition of an absorption enhancer, it has been better recognized as a new site for drug administration. However, conventional oral preparations are not necessarily satisfactory in that they disintegrate and dissolve before the arrival at the large intestine, resulting that a physiologically active polypeptide or oligonucleotide which is administered orally is easily degraded by a hydrolytic enzyme in the small intestine. Therefore, development of a delivery technology for the large intestine has to date been tried from several different angles.
For example, there have been reported an oral preparation targeting the large intestine, which is prepared by combining a polymer soluble only at the pH of 5.5 or above and an insoluble polymer (EP, 49590, A); a solid oral preparation coated with a suitable amount of an anionic polymer soluble at the pH of 7.0 or above (trade name: Eudragit S, a product of Rxc3x6hm GmbH) (WO83/00435); an oral preparation coated with an anionic polymer soluble at the pH of 7.0 or above (trade name: Eudragit S, a product of Rxc3x6hm GmbH) and a methacrylate copolymer poorly water soluble (trade name: Eudragit RS, a product of Rxc3x6hm GmbH) at a suitable composition rate (EP, 225189, A); an osmotic-pump preparation coated with an enteric polymer; an oral pharmaceutical preparation reaching the large intestine, which is covered with an inner coat soluble at the pH of 7.0 or above, an intermediate coat made of a gelatinized polymer, and a stomach-proof outer coat soluble at the pH of 5.5 or above (JP, 4-501411, A); and so forth. Further, several delivery technologies using a coating polymer for a pharmaceutical additive have been reported (WO 90/13286; JP, 9-87169, A; WO 95/28963).
The inventors of the present invention have also proposed an oral preparation of releasing at lower intestinal tracts, having a high specificity to the large intestine (WO 94/10983; JP, 10-152431, A). This preparation is characterized in that it consists of double-coating structure in which the case of tablets compressively molded, granules, or capsules filled with powder of a liquid preparation is coated with an inner layer consisting of a cationic copolymer and an outer layer consisting of an anionic copolymer. This preparation has a very good specificity to the large intestine and enabled to release a drug targeted to the large intestine in a more reliable and rapid way.
The development of these delivery technologies targeting the large intestine makes it possible to deliver a peptide drug or a nucleotide drug in an unchanged state and to utilize the large intestine as a new absorption site, though a satisfactory absorption efficiency is not necessarily obtained in a polymer drug like peptides. It is considered that this comes from the reason that, owing to a tight cell function in a large-intestinal part, the absorption of a highly hydrophilic polymer peptide drug is usually difficult.
Thus, modifications to obtain better absorption from a large-intestinal mucous membrane have also been tried. One of them is a method to use an absorption enhancer which is widely used to facilitate a transmucosal absorption in preparation such as an intranasal, intravaginal, rectal or oral preparation. As for an absorption enhancer, mainly reported are bile acid salts having a surfactant action (JP, 59-130820, A), ionic or non-ionic surfactants (JP, 4-247034, A), chelating agents, medium chain fatty acid salts (U.S. Pat. No. 4,476,116, A), alkali metal glycyrrhinates (JP, 2-42027, A), azacycloalkane derivatives (JP, 6-43390, B) and the like.
However, the present situation is that an absorption enhancer for a transmucosal developed so far is yet to be fully used for the large intestine compared with the intranasal and other transmucosal use. As the reason for this, it is pointed out that, first, in case of the administration in a solution state conventional absorption enhancers are mostly rapid in the absorption and are not enough in durability. Further, even if in the case that durability of an absorption-promoting action is strong, in the state of an aqueous solution, the administration can only be made in a method like intraintestinal one, being inferior in usability. On the other hand, in the case that one in a powder state is applied to an oral preparation with a disintegration property in the large-intestinal environment, solubility of a drug or an absorption enhancer is not enough due to the insufficiency of the amount of water in the large intestine. These become reasons that other mucous membrane absorption enhancers can not easily be applied to the large-intestinal use.
Thus, although the large intestine is noted as a preferable absorption site in a digestive tract for physiologically active polypeptides or oligonucleotides, a fully satisfactory preparation technology has not yet been developed.
The object of the invention therefore is to provide an absorption enhancer for the large intestine, having a highly absorption enhancer effect to solve the above problems, especially an absorption enhancer for the large intestine suitable for an oral preparation having a disintegration property in the large intestine.
The inventors, by conducting extensive researches to solve the above problems, found out that they can be solved by mixing a hydrophilic medium with an absorption enhancer and completed the invention.
The invention is based on a finding, through a screening of existing absorption enhancers by rat in situ loop experiments for evaluating the absorption of a drug in the rat large intestine, that the absorption enhancer effect is increased by mixing absorption enhancers such as azacycloalkane derivatives, medium-chain fatty acids or bile acids with a hydrophilic medium such as polyethylene glycol or glycerin, which alone do not show any absorption-promoting effect. Further, the invention is based on a finding that owing to the achieved preparation in a state wherein a poorly water soluble absorption enhancer is dissolved by a hydrophilic medium, which can strongly absorb water in a large-intestine tract, a water-soluble peptide type drug can rapidly be eluted from the preparation.
Namely, the invention relates to an absorption enhancer for the large intestine containing a hydrophilic medium and an absorption enhancer.
Also, the invention relates to the absorption enhancer for the large intestine wherein the hydrophilic medium is polyethylene glycol with the average molecular weight in the range of 190 to 630 or glycerin.
The invention also relates to the absorption enhancer for the large intestine wherein the absorption enhancer is one or more types selected from the group consisting of azacycloalkane derivatives, bile acid salts and medium-chain fatty acid salts.
Further, the invention also relates to the absorption enhancer for the large intestine wherein the azacycloalkane derivative is 1-[2-(decylthio)ethyl]azacyclopentan-2-one.
Also, the invention relates to the absorption enhancer for the large intestine wherein the bile acid salt is one or more types selected from the group consisting of sodium cholate, sodium glycocholate, sodium taurocholate, sodium deoxycholate and sodium chenodeoxycholate.
The invention also relates to the absorption enhancer for the large intestine wherein the medium-chain fatty acid salt is one or more types selected from alkaline metal salts of capric acid, caprylic acid or caproic acid.
Further, the invention relates to an oral preparation containing the above absorption enhancer for the large intestine.
Furthermore, the invention relates to an oral preparation wherein the physiologically active polypeptide or oligonucleotide is contained as an active ingredient.